PROJECT SUMMARY/ABSTRACT How do in utero opioid exposure and early adversity affect a child's neurodevelopmental and health outcomes? The simplicity of this question masks the complex and multifaceted nature of human neurodevelopment, and the variety of environmental influences that can exacerbate or moderate the effects of in utero substance exposure. From conception to age 10, our brain undergoes remarkable structural and functional change. Processes including myelination and synaptogenesis are at their peak throughout this age span, contributing to the emergence of nearly all cognitive and behavioral skills, and responsive to both early substance exposures and environmental stimuli. In the context of fetal opioid exposure, this often co-occurs with other maternal substance use (alcohol, tobacco, marijuana), as well as related pre- and post-natal factors including maternal mental health concerns, supportive or adverse family environments, low socioeconomic status (SES), inter-partner violence, and caregiving quality and quantity. Despite increased efforts to understand the neurodevelopmental sequela of in utero opioid and other substance exposure on long-term behavioral, cognitive, and societal outcomes, important questions remain, specifically, 1. How brain growth is disrupted by fetal substance and related pre and post-natal exposures; and 2. How are these disrupted growth patterns causally related to later cognitive and behavioral outcomes? This proposal seeks to formulate our approach to addressing these key questions, and decipher the individual and cumulative effect of these intertwined pre- and post-natal exposures on child neurodevelopment. By bringing together leading experts in child development and adversity, pediatric neuroimaging, maternal, fetal, and child abuse medicine, longitudinal and functional statistics, and public health, strategically located US states and counties hardest hit by the current opioid crisis, we will articulate our vision of the larger HEALthy Brain & Child Development study, and lay the foundation for our participation in three incremental steps. First, we will address the legal, ethical, and mother-child care and support concerns implicit in this study by leveraging our team's past experience in family adversity, child abuse, and fetal substance exposure research. Next, we will integrate across our areas of neuroimaging expertise to develop, implement, and harmonize a multi-modal MRI and EEG protocol to assess maturing brain structure, function, and connectivity. This neuroimaging protocol will be paired with extensive neurocognitive, sociodemographic, physical health, family and medical history, anthropometric, and biospecimen data collection to quantify the individual, cumulative, and interactive effects of a child's substance and environment on their overall health and neurodevelopment. Finally, we will develop and test advanced statistical approaches to model and analyze this multidimensional and longitudinal data, taking into account the likely sparse and unbalanced nature of the measurements. Together, these steps lay the foundation for a broad and large-scale study to examine the impact of exposure to substances and early adversity on a child's neural, physical, and behavioral development.